title: Anti-proliferative withanolides from the Solanaceae: a structure-activity study.
abstract: As part of our search for bioactive compounds from plant biodiversity, 29 withanolides (1, 3-6, 9, 12-18, and20-35) were recently isolated from three members of the Solanaceae:Physalis longifolia, Vassobia breviflora, andWithania somnifera. Six derivatives (2, 7, 8, 10, 11, and19) were prepared from these naturally occurring withanolides. All compounds (1-35) were evaluated forin vitroanti-proliferative activity against an array of cell lines [melanoma cell lines (B16F10, SKMEL28); human head and neck squamous cell carcinomas (HNSCC) cell lines (JMAR, MDA1986, DR081-1); breast cancer cell line (Hs578T), and non-malignant human cell line (MRC5)]. This led to the discovery of 15 withanolides, with IC50 values in the range of 0.067-17.4 µM, including withaferin A1, withaferin A 4,27-diacetate2, 27-O-glucopyranosylwithaferin A3, withalongolide H4, withalongolide C5, withalongolide A6, withalongolide A 4,27-diacetate7, withalongolide A 4,19,27-triacetate8, withalongolide B9, withalongolide B 4-acetate10, withalongolide B 4,19-diacetate11, withalongolide D16, withalongolide E17, withalongolide G21, and 2,3-dihydrowithaferin A 3-O-sulfate22). In order to update the growing literature on withanolides and their activities, we summarized the distribution, structural types and anti-proliferative activities for all published withanolides to date. The structure-activity relationship analysis (SARA) confirmed the importance of the presence of a Δ2-1-oxo- functionality in ring A, a 5β,6β-epoxy or 5α-chloro-6β-hydroxy groupings in ring B, and nine carbon side chain with a lactone moiety for cytotoxic activity. Conversely, the SARA indicated that the -OH or -OR groups at C-4, 7, 11, 12, 14, 15, 16, 17, 18, 19, 20, 23, 24, 27, 28 were not contributors to the observed anti-proliferative activity within the systems analyzed.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS 66045, United States.
authors.forename: Huaping
authors.initials: H
authors.lastname: Zhang
authors.forename: Abbas K
authors.initials: AK
authors.lastname: Samadi
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cohen
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Timmermann
keywords: Physalis longifolia; Solanaceae; Vassobia breviflora; Withania somnifera; anti-proliferative; structure classifcation; structure-activity relationship; withanolide